In an "Information Age" when we are continually flooded with multiple simultaneous inputs, many elderly people struggle with seemingly simple tasks, such as navigating their bank's phone tree, using the remote to watch TV or DVDs, using the increasingly essential computer and internet, or driving the car on ever more complex roadways. We all need our "executive abilities" far more than we did even 20 years ago, and this is a particular challenge for the elderly. A core feature of cognitive aging is the decline in executive functions mediated by the prefrontal cortex. These functions include the ability to keep in mind what has just occurred, or bring to mind knowledge from the past, and use this temporary information to guide behavior. This represented information is critical for inhibiting inappropriate responses and overcoming distraction and interference from previous, now irrelevant memories. Prefrontal executive functions are key for planning, maintaining attention, and storing and recalling memories, especially when it is an effortful process. Although prefrontal executive dysfunction is a characteristic and disabling feature of aging, no treatment has been developed to date-or even tested, to our knowledge-for the amelioration of these symptoms. Yet, two decades of research in animals has demonstrated that the executive functions of the prefrontal cortex can be improved by alpha-2 adrenoreceptor agonists. The alpha-2A-agonist, guanfacine, is well-tolerated and has already demonstrated benefit in patients with attention deficit hyperactivity disorder. However, guanfacine has thus far not been tested for its ability to restore executive function in elderly adults, despite the evidence from preclinical research that the elderly are the most likely to experience its benefit. This proposal aims to determine whether low doses of the alpha-2A-agonist guanfacine can improve deficits in prefrontally-mediated executive functions in healthy elderly (=75 years) subjects. Subjects (N=90) will be randomly assigned to receive placebo or guanfacine at one of two dose levels: 0.1 mg daily, or 0.5 mg daily in double-blind fashion for 12 weeks. Subjects will be assessed using composite measures of prefrontal executive function and recognition memory function, a clinical global impression of change, and a quality of life measure. This Pilot Clinical Trial will provide essential preliminary data for a subsequent full-scale trial of guanfacine for prefrontally-mediated cognitive dysfunction in elderly subjects. [unreadable] [unreadable]